Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. (DIAN-TU)

The purpose of this study is to assess the safety, tolerability, biomarker and cognitive efficacy of gantenerumab and solanezumab in subjects who are known to have an Alzheimer's disease-causing mutation by determining if treatment with the study drug improves cognitive outcomes and disease-related biomarkers.

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:

Assess cognitive efficacy of gantenerumab and solanezumab in individuals with mutations causing dominantly inherited AD as measured by change in the DIAN-TU cognitive composite score. Comparisons will not be made between the two drug treatments. [ Time Frame: Baseline and Week 52, 104, 156, and 208 ] [ Designated as safety issue: No ]

The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with autosomal dominant Alzheimer's disease have very high penetrance (near 100%). This study will target individuals who are either known to have a disease-causing mutation or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and with each mutation (Ryman et al., 2014), an age at onset is determined for each affected parent or mutation. This study will enroll subjects who are either asymptomatic and are within a specific window of time of expected age of onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease.

The ability to identify individuals destined to develop Alzheimer's disease (AD) within the next 10-15 years with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Although there are differences between dominantly inherited AD and the more common age-associated sporadic disease, the results of the early intervention in this study will have implications for future studies and treatments in sporadic AD. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Many of the subjects in this study will not yet have any cognitive symptoms of AD; they will be "asymptomatic" carriers of mutations that cause Autosomal Dominant Alzheimer's disease and would be expected to perform normally on standard cognitive and functional testing. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation or not, some of the at-risk individuals enrolled in this study will not have the disease causing mutations; they will be "mutation negative". It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be pressured into genetic testing to learn their genetic status in order to be eligible for the trial). These mutation negative individuals will be assigned to the placebo group; subjects and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be double blinded for placebo and for mutation status, except for mutation positive subjects who are aware of their genetic status. Two different therapies will be tested in order to increase the likelihood that an effective treatment will be discovered. They were selected for this trial based on mechanism of action and available data on efficacy and safety profile.

The study design includes a pooled placebo arm shared by all treatment groups. Mutation positive subjects will be randomized to one of the four study arms (gantenerumab:gantenerumab placebo:solanezumab:solanezumab placebo) in an overall 3:1:3:1 ratio for active drug:placebo. Mutation negative subjects will all receive placebo. Importantly, subjects and study staff will not be blinded as to which treatment group each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo arms. Biomarker data will be analyzed for prespecified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. The primary cognitive endpoint will be the same for both treatment arms. Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study drug engages its biological targets. This biomarker approach is particularly important in this study as most study subjects will be cognitively normal at the time of enrollment and most will remain cognitively normal during the first 2 years of the study. The cognitive composite is designed to assess subtle cognitive changes that may be detectable before the onset of dementia. The four year cognitive endpoint will allow for analysis of these subtle cognitive changes.

Eligibility

Ages Eligible for Study:

18 Years to 80 Years (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Between 18-80 years of age

Individuals who know they have an Alzheimer's disease-causing mutation or are unaware of their genetic status and have a 50% chance of having an autosomal dominant Alzheimer's disease (ADAD) mutation (e.g. parent or sibling with a known AD-causing mutation)

Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset

For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide).

Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.

Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion.

Exclusion Criteria:

History or presence of brain MRI scans indicative of any other significant abnormality

Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the past six months.

History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.

Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial.

Subjects unable to complete all study related testing, including implanted metal that cannot be removed for MRI scanning, required anticoagulation and pregnancy.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01760005